title: Decorin causes autophagy in endothelial cells via Peg3.
abstract: Soluble decorin affects the biology of several receptor tyrosine kinases by triggering receptor internalization and degradation. We found that decorin induced paternally expressed gene 3 (Peg3), an imprinted tumor suppressor gene, and that Peg3 relocated into autophagosomes labeled by Beclin 1 and microtubule-associated light chain 3. Decorin evoked Peg3-dependent autophagy in both microvascular and macrovascular endothelial cells leading to suppression of angiogenesis. Peg3 coimmunoprecipitated with Beclin 1 and LC3 and was required for maintaining basal levels of Beclin 1. Decorin, via Peg3, induced transcription of Beclin 1 and microtubule-associated protein 1 light chain 3 alpha genes, thereby leading to a protracted autophagic program. Mechanistically, decorin interacted with VEGF receptor 2 (VEGFR2) in a region overlapping with its natural ligand VEGFA, and VEGFR2 was required for decorin-evoked Beclin 1 and microtubule-associated protein 1 light chain 3 alpha expression as well as for Peg3 induction in endothelial cells. Moreover, decorin induced VEGFR2-dependent mitochondrial fragmentation and loss of mitochondrial membrane potential. Thus, we have unveiled a mechanism for a secreted proteoglycan in inducing Peg3, a master regulator of macroautophagy in endothelial cells.
authors.affiliation: Department of Pathology, Anatomy and Cell Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Simone
authors.initials: S
authors.lastname: Buraschi
authors.forename: Thomas
authors.initials: T
authors.lastname: Neill
authors.forename: Atul
authors.initials: A
authors.lastname: Goyal
authors.forename: Chiara
authors.initials: C
authors.lastname: Poluzzi
authors.forename: James
authors.initials: J
authors.lastname: Smythies
authors.forename: Rick T
authors.initials: RT
authors.lastname: Owens
authors.forename: Liliana
authors.initials: L
authors.lastname: Schaefer
authors.forename: Annabel
authors.initials: A
authors.lastname: Torres
authors.forename: Renato V
authors.initials: RV
authors.lastname: Iozzo
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D001343:Autophagy / Q000502:physiology*; D000071186:Beclin-1; D002478:Cells, Cultured; D058575:Decorin / Q000378:metabolism / Q000502:physiology*; D004730:Endothelium, Vascular / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism / Q000502:physiology*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D015398:Signal Transduction; D015533:Transcriptional Activation; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; C546878:DCN protein, human; C546879:Dcn protein, mouse; D058575:Decorin; D051741:Kruppel-Like Transcription Factors; C477012:MAP1LC3A protein, human; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; C490820:PEG3 protein, human; C097901:Peg3 protein, mouse; D040301:Vascular Endothelial Growth Factor Receptor-2
keywords: microvascular endothelial cells; porcine aortic endothelial cells; small leucine-rich proteoglycan